[unreadable] The objective of this proposal is to investigate the molecular mechanisms of dietary lipid absorption and the role of fatty acid tranport protein 4 (FATP4), hypothesized to be the dominant small intestine long-chain fatty acid transporter. Because FATP4 null mice die shortly after birth, the role of FATP4 in dietary lipid absorption has not been assessed. Using a transgene expressed exclusively in skin, FATP4 null mice have been rescued and express no FATP4 in the intestine. These mice consume 10% more food per gram body weight than controls, yet manifest reduced serum triglycerides and cholesterol, differences that become more pronounced after consumption of a high-fat diet. These results suggest defective lipid absorption in rescued mutants, which may be partially compensated. The specific aims of this project are to determine the role of FATP4 in dietary fatty acid absorption, cholesterol homeostasis, and lipid processing through in vivo absorption, metabolic, and packaging studies. The necessity of the acyl-CoA synthetase activity of FATP4 in vivo will be investigated using a transgene with an inactive acyl-CoA synthetase domain bred onto the FATP4 null mouse. Finally, oligomerization of FATP4 will be investigated through immunoprecipitation and examination of dominant-negative activity of a mutated FATP4. These studies will advance our understanding of how dietary lipids are absorbed from the intestines and how FATP4 functions in this regard. \ [unreadable] These studies will be conducted at Washington University and will provide the training and necessary skills for the investigator to make the transition to independent research under the supervision of Nicholas Davidson, with additional scientific and career advice provided from an advisory committee. [unreadable] Results from this research will help to understand the mechanisms by which dietary lipids are absorbed from the intestine and may help to understand obesity. Obesity is currently the second leading cause of preventable disease and death in the United States behind cigarette smoking. [unreadable] [unreadable] [unreadable]